First clinical experiences with inclisiran in a real-world setting

Background and objective: Inclisiran is the first-in-class small interfering RNA (siRNA) PCSK9 inhibitor. In clinical trials inclisiran showed effective and sustained LDL-C reduction of ± 50 %. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice. Methods:We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level. Results: We analysed 65 patients (36 women), median [25th percentile; 75th percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n = 45) showed a LDL-C decrease of 38 [-49;-33] %. Patients who used statins as co-medication (n = 15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45 % vs 38 %). However, patients who switched from mAbs to inclisiran (group 2, n = 20) had an increase in LDL-C of 38 [+4; +97] %. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months. Conclusion: Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs.</p

Individualized dosing of evinacumab is predicted to yield reductions in drug expenses

Background: Evinacumab is a first-in-class inhibitor of angiopoietin‐like protein 3 (ANGPTL3) for treatment of the rare disease homozygous familial hypercholesterolemia (HoFH). With projected drug costs of $450,000 per person per year, the question rises if cost-efficacy of evinacumab can be further improved. Objectives: To develop an individualized dosing regimen te reduce drug expenses. Methods: Using the clinical and pharmacological data as provided by the license holder, we developed an alternative dosing regimen in silico based on the principles of reduction of wastage by dosing based on weight bands rather than a linear milligram per kilogram body weight (mg/kg) dosing regimen, as well as dose individualization guided by low density lipoprotein cholesterol (LDL-C) response. Results: We found that the average quantity of drug used for a dose could be reduced by 34% without predicted loss in efficacy (LDL-C reduction 24 weeks after treatment initiation). Conclusion: Dose reductions without compromising efficacy seem feasible. We call for implementation and prospective evaluation of this strategy to reduce treatment costs of HoFH.</p

Sex Differences in Familial Hypercholesterolemia

Purpose of Review: This review aims to summarize the existing research on sex differences in familial hypercholesterolemia (FH) across the lifespan. Recent Findings: From childhood onward, total- and low-density lipoprotein cholesterol (LDL-C) levels in girls are higher than those in boys with FH. By the age of 30 years, women with FH have a higher LDL-C burden than men. In adulthood, women are diagnosed later than men, receive less lipid-lowering treatment, and consequently have higher LDL-C levels. An excessive atherosclerotic cardiovascular disease risk is reported in young female compared to male FH patients. The periods of pregnancy and breastfeeding contribute to treatment loss and increased cholesterol burden. Summary: Earlier initiation of treatment, especially in girls with FH, and lifelong treatment during all life stages are important. Future research should aim to recruit both women and men, report sex-specific data, and investigate the impact of the female life course on cardiovascular outcomes. Future guidelines should include sex-specific aspects. Graphical abstract: [Figure not available: see fulltext.].</p

Sex differences in efficacy and safety of PCSK9 monoclonal antibodies:A real-world registry

Background and aims: Proprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care. Methods: All patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded. Results: We analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p &lt; 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p&lt;0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46). Conclusions: In clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism.</p